Skip to main content
PMC home page
The Journal of Cell Biology logoLink to The Journal of Cell Biology
. 1987 Dec 1;105(6):2861–2876. doi: 10.1083/jcb.105.6.2861

Role of transforming growth factor-beta in the development of the mouse embryo

PMCID: PMC2114724  PMID: 3320058

Abstract

Using immunohistochemical methods, we have investigated the role of transforming growth factor-beta (TGF-beta) in the development of the mouse embryo. For detection of TGF-beta in 11-18-d-old embryos, we have used a polyclonal antibody specific for TGF-beta type 1 and the peroxidase-antiperoxidase technique. Staining of TGF-beta is closely associated with mesenchyme per se or with tissues derived from mesenchyme, such as connective tissue, cartilage, and bone. TGF-beta is conspicuous in tissues derived from neural crest mesenchyme, such as the palate, larynx, facial mesenchyme, nasal sinuses, meninges, and teeth. Staining of all of these tissues is greatest during periods of morphogenesis. In many instances, intense staining is seen in mesenchyme when critical interactions with adjacent epithelium occur, as in the development of hair follicles, teeth, and the submandibular gland. Marked staining is also seen when remodeling of mesenchyme or mesoderm occurs, as during formation of digits from limb buds, formation of the palate, and formation of the heart valves. The presence of TGF-beta is often coupled with pronounced angiogenic activity. The histochemical results are discussed in terms of the known biochemical actions of TGF-beta, especially its ability to control both synthesis and degradation of both structural and adhesion molecules of the extracellular matrix.

Full Text

The Full Text of this article is available as a PDF (22.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Assoian R. K., Frolik C. A., Roberts A. B., Miller D. M., Sporn M. B. Transforming growth factor-beta controls receptor levels for epidermal growth factor in NRK fibroblasts. Cell. 1984 Jan;36(1):35–41. doi: 10.1016/0092-8674(84)90071-0. [DOI] [PubMed] [Google Scholar]
  2. Assoian R. K., Komoriya A., Meyers C. A., Miller D. M., Sporn M. B. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983 Jun 10;258(11):7155–7160. [PubMed] [Google Scholar]
  3. Auffray C., Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. doi: 10.1111/j.1432-1033.1980.tb06030.x. [DOI] [PubMed] [Google Scholar]
  4. Centrella M., McCarthy T. L., Canalis E. Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone. J Biol Chem. 1987 Feb 25;262(6):2869–2874. [PubMed] [Google Scholar]
  5. Cheifetz S., Weatherbee J. A., Tsang M. L., Anderson J. K., Mole J. E., Lucas R., Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell. 1987 Feb 13;48(3):409–415. doi: 10.1016/0092-8674(87)90192-9. [DOI] [PubMed] [Google Scholar]
  6. Chiang C. P., Nilsen-Hamilton M. Opposite and selective effects of epidermal growth factor and human platelet transforming growth factor-beta on the production of secreted proteins by murine 3T3 cells and human fibroblasts. J Biol Chem. 1986 Aug 15;261(23):10478–10481. [PubMed] [Google Scholar]
  7. Crossin K. L., Hoffman S., Grumet M., Thiery J. P., Edelman G. M. Site-restricted expression of cytotactin during development of the chicken embryo. J Cell Biol. 1986 May;102(5):1917–1930. doi: 10.1083/jcb.102.5.1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  9. Derynck R., Jarrett J. A., Chen E. Y., Eaton D. H., Bell J. R., Assoian R. K., Roberts A. B., Sporn M. B., Goeddel D. V. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985 Aug 22;316(6030):701–705. doi: 10.1038/316701a0. [DOI] [PubMed] [Google Scholar]
  10. Derynck R., Jarrett J. A., Chen E. Y., Goeddel D. V. The murine transforming growth factor-beta precursor. J Biol Chem. 1986 Apr 5;261(10):4377–4379. [PubMed] [Google Scholar]
  11. Derynck R., Rhee L. Sequence of the porcine transforming growth factor-beta precursor. Nucleic Acids Res. 1987 Apr 10;15(7):3187–3187. doi: 10.1093/nar/15.7.3187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Duband J. L., Dufour S., Hatta K., Takeichi M., Edelman G. M., Thiery J. P. Adhesion molecules during somitogenesis in the avian embryo. J Cell Biol. 1987 May;104(5):1361–1374. doi: 10.1083/jcb.104.5.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Edwards D. R., Murphy G., Reynolds J. J., Whitham S. E., Docherty A. J., Angel P., Heath J. K. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J. 1987 Jul;6(7):1899–1904. doi: 10.1002/j.1460-2075.1987.tb02449.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ellingsworth L. R., Brennan J. E., Fok K., Rosen D. M., Bentz H., Piez K. A., Seyedin S. M. Antibodies to the N-terminal portion of cartilage-inducing factor A and transforming growth factor beta. Immunohistochemical localization and association with differentiating cells. J Biol Chem. 1986 Sep 15;261(26):12362–12367. [PubMed] [Google Scholar]
  15. Fine A., Goldstein R. H. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem. 1987 Mar 15;262(8):3897–3902. [PubMed] [Google Scholar]
  16. Fitzharris T. P., Markwald R. R. Cellular migration through the cardiac jelly matrix: a stereoanalysis by high-voltage electron microscopy. Dev Biol. 1982 Aug;92(2):315–329. doi: 10.1016/0012-1606(82)90178-6. [DOI] [PubMed] [Google Scholar]
  17. Florini J. R., Roberts A. B., Ewton D. Z., Falen S. L., Flanders K. C., Sporn M. B. Transforming growth factor-beta. A very potent inhibitor of myoblast differentiation, identical to the differentiation inhibitor secreted by Buffalo rat liver cells. J Biol Chem. 1986 Dec 15;261(35):16509–16513. [PubMed] [Google Scholar]
  18. Grobstein C. Mechanisms of organogenetic tissue interaction. Natl Cancer Inst Monogr. 1967 Sep;26:279–299. [PubMed] [Google Scholar]
  19. Hill D. J., Strain A. J., Milner R. D. Presence of transforming growth factor-beta-like activity in multiple fetal rat tissues. Cell Biol Int Rep. 1986 Dec;10(12):915–922. doi: 10.1016/0309-1651(86)90111-6. [DOI] [PubMed] [Google Scholar]
  20. Holland P. W., Harper S. J., McVey J. H., Hogan B. L. In vivo expression of mRNA for the Ca++-binding protein SPARC (osteonectin) revealed by in situ hybridization. J Cell Biol. 1987 Jul;105(1):473–482. doi: 10.1083/jcb.105.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Icardo J. M., Manasek F. J. An indirect immunofluorescence study of the distribution of fibronectin during the formation of the cushion tissue mesenchyme in the embryonic heart. Dev Biol. 1984 Feb;101(2):336–345. doi: 10.1016/0012-1606(84)90147-7. [DOI] [PubMed] [Google Scholar]
  22. Ignotz R. A., Endo T., Massagué J. Regulation of fibronectin and type I collagen mRNA levels by transforming growth factor-beta. J Biol Chem. 1987 May 15;262(14):6443–6446. [PubMed] [Google Scholar]
  23. Ignotz R. A., Massagué J. Cell adhesion protein receptors as targets for transforming growth factor-beta action. Cell. 1987 Oct 23;51(2):189–197. doi: 10.1016/0092-8674(87)90146-2. [DOI] [PubMed] [Google Scholar]
  24. Ignotz R. A., Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337–4345. [PubMed] [Google Scholar]
  25. Ikeda T., Lioubin M. N., Marquardt H. Human transforming growth factor type beta 2: production by a prostatic adenocarcinoma cell line, purification, and initial characterization. Biochemistry. 1987 May 5;26(9):2406–2410. doi: 10.1021/bi00383a002. [DOI] [PubMed] [Google Scholar]
  26. Jetten A. M. Action of retinoids and phorbol esters on cell growth and the binding of epidermal growth factor. Ann N Y Acad Sci. 1981 Feb 27;359:200–217. doi: 10.1111/j.1749-6632.1981.tb12748.x. [DOI] [PubMed] [Google Scholar]
  27. Laiho M., Saksela O., Andreasen P. A., Keski-Oja J. Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta. J Cell Biol. 1986 Dec;103(6 Pt 1):2403–2410. doi: 10.1083/jcb.103.6.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lee D. C., Rochford R., Todaro G. J., Villarreal L. P. Developmental expression of rat transforming growth factor-alpha mRNA. Mol Cell Biol. 1985 Dec;5(12):3644–3646. doi: 10.1128/mcb.5.12.3644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lund L. R., Riccio A., Andreasen P. A., Nielsen L. S., Kristensen P., Laiho M., Saksela O., Blasi F., Danø K. Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblasts. EMBO J. 1987 May;6(5):1281–1286. doi: 10.1002/j.1460-2075.1987.tb02365.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Madri J. A., Pratt B. M. Endothelial cell-matrix interactions: in vitro models of angiogenesis. J Histochem Cytochem. 1986 Jan;34(1):85–91. doi: 10.1177/34.1.2416801. [DOI] [PubMed] [Google Scholar]
  31. Madri J. A., Williams S. K. Capillary endothelial cell cultures: phenotypic modulation by matrix components. J Cell Biol. 1983 Jul;97(1):153–165. doi: 10.1083/jcb.97.1.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mason I. J., Murphy D., Münke M., Francke U., Elliott R. W., Hogan B. L. Developmental and transformation-sensitive expression of the Sparc gene on mouse chromosome 11. EMBO J. 1986 Aug;5(8):1831–1837. doi: 10.1002/j.1460-2075.1986.tb04434.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Massagué J., Cheifetz S., Endo T., Nadal-Ginard B. Type beta transforming growth factor is an inhibitor of myogenic differentiation. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8206–8210. doi: 10.1073/pnas.83.21.8206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Massagué J. The TGF-beta family of growth and differentiation factors. Cell. 1987 May 22;49(4):437–438. doi: 10.1016/0092-8674(87)90443-0. [DOI] [PubMed] [Google Scholar]
  35. Newgreen D., Thiery J. P. Fibronectin in early avian embryos: synthesis and distribution along the migration pathways of neural crest cells. Cell Tissue Res. 1980;211(2):269–291. doi: 10.1007/BF00236449. [DOI] [PubMed] [Google Scholar]
  36. Olson E. N., Sternberg E., Hu J. S., Spizz G., Wilcox C. Regulation of myogenic differentiation by type beta transforming growth factor. J Cell Biol. 1986 Nov;103(5):1799–1805. doi: 10.1083/jcb.103.5.1799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Padgett R. W., St Johnston R. D., Gelbart W. M. A transcript from a Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family. Nature. 1987 Jan 1;325(6099):81–84. doi: 10.1038/325081a0. [DOI] [PubMed] [Google Scholar]
  38. Pfeilschifter J., Mundy G. R. Modulation of type beta transforming growth factor activity in bone cultures by osteotropic hormones. Proc Natl Acad Sci U S A. 1987 Apr;84(7):2024–2028. doi: 10.1073/pnas.84.7.2024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Postlethwaite A. E., Keski-Oja J., Moses H. L., Kang A. H. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987 Jan 1;165(1):251–256. doi: 10.1084/jem.165.1.251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Proper J. A., Bjornson C. L., Moses H. L. Mouse embryos contain polypeptide growth factor(s) capable of inducing a reversible neoplastic phenotype in nontransformed cells in culture. J Cell Physiol. 1982 Feb;110(2):169–174. doi: 10.1002/jcp.1041100210. [DOI] [PubMed] [Google Scholar]
  41. Rickmann M., Fawcett J. W., Keynes R. J. The migration of neural crest cells and the growth of motor axons through the rostral half of the chick somite. J Embryol Exp Morphol. 1985 Dec;90:437–455. [PubMed] [Google Scholar]
  42. Roberts A. B., Anzano M. A., Lamb L. C., Smith J. M., Sporn M. B. Antagonistic actions of retinoic acid and dexamethasone on anchorage-independent growth and epidermal growth factor binding of normal rat kidney cells. Cancer Res. 1984 Apr;44(4):1635–1641. [PubMed] [Google Scholar]
  43. Roberts A. B., Sporn M. B., Assoian R. K., Smith J. M., Roche N. S., Wakefield L. M., Heine U. I., Liotta L. A., Falanga V., Kehrl J. H. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4167–4171. doi: 10.1073/pnas.83.12.4167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Robey P. G., Young M. F., Flanders K. C., Roche N. S., Kondaiah P., Reddi A. H., Termine J. D., Sporn M. B., Roberts A. B. Osteoblasts synthesize and respond to transforming growth factor-type beta (TGF-beta) in vitro. J Cell Biol. 1987 Jul;105(1):457–463. doi: 10.1083/jcb.105.1.457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rovasio R. A., Delouvee A., Yamada K. M., Timpl R., Thiery J. P. Neural crest cell migration: requirements for exogenous fibronectin and high cell density. J Cell Biol. 1983 Feb;96(2):462–473. doi: 10.1083/jcb.96.2.462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Seyedin S. M., Segarini P. R., Rosen D. M., Thompson A. Y., Bentz H., Graycar J. Cartilage-inducing factor-B is a unique protein structurally and functionally related to transforming growth factor-beta. J Biol Chem. 1987 Feb 15;262(5):1946–1949. [PubMed] [Google Scholar]
  47. Seyedin S. M., Thomas T. C., Thompson A. Y., Rosen D. M., Piez K. A. Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc Natl Acad Sci U S A. 1985 Apr;82(8):2267–2271. doi: 10.1073/pnas.82.8.2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Seyedin S. M., Thompson A. Y., Bentz H., Rosen D. M., McPherson J. M., Conti A., Siegel N. R., Galluppi G. R., Piez K. A. Cartilage-inducing factor-A. Apparent identity to transforming growth factor-beta. J Biol Chem. 1986 May 5;261(13):5693–5695. [PubMed] [Google Scholar]
  49. Sporn M. B., Roberts A. B. Role of retinoids in differentiation and carcinogenesis. Cancer Res. 1983 Jul;43(7):3034–3040. [PubMed] [Google Scholar]
  50. Sporn M. B., Roberts A. B., Shull J. H., Smith J. M., Ward J. M., Sodek J. Polypeptide transforming growth factors isolated from bovine sources and used for wound healing in vivo. Science. 1983 Mar 18;219(4590):1329–1331. doi: 10.1126/science.6572416. [DOI] [PubMed] [Google Scholar]
  51. Sporn M. B., Roberts A. B., Wakefield L. M., Assoian R. K. Transforming growth factor-beta: biological function and chemical structure. Science. 1986 Aug 1;233(4763):532–534. doi: 10.1126/science.3487831. [DOI] [PubMed] [Google Scholar]
  52. Sporn M. B., Roberts A. B., Wakefield L. M., de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol. 1987 Sep;105(3):1039–1045. doi: 10.1083/jcb.105.3.1039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Strickland S., Reich E., Sherman M. I. Plasminogen activator in early embryogenesis: enzyme production by trophoblast and parietal endoderm. Cell. 1976 Oct;9(2):231–240. doi: 10.1016/0092-8674(76)90114-8. [DOI] [PubMed] [Google Scholar]
  54. Termine J. D., Kleinman H. K., Whitson S. W., Conn K. M., McGarvey M. L., Martin G. R. Osteonectin, a bone-specific protein linking mineral to collagen. Cell. 1981 Oct;26(1 Pt 1):99–105. doi: 10.1016/0092-8674(81)90037-4. [DOI] [PubMed] [Google Scholar]
  55. Thaller C., Eichele G. Identification and spatial distribution of retinoids in the developing chick limb bud. Nature. 1987 Jun 18;327(6123):625–628. doi: 10.1038/327625a0. [DOI] [PubMed] [Google Scholar]
  56. Van Obberghen-Schilling E., Kondaiah P., Ludwig R. L., Sporn M. B., Baker C. C. Complementary deoxyribonucleic acid cloning of bovine transforming growth factor-beta 1. Mol Endocrinol. 1987 Oct;1(10):693–698. doi: 10.1210/mend-1-10-693. [DOI] [PubMed] [Google Scholar]
  57. Varga J., Jimenez S. A. Stimulation of normal human fibroblast collagen production and processing by transforming growth factor-beta. Biochem Biophys Res Commun. 1986 Jul 31;138(2):974–980. doi: 10.1016/s0006-291x(86)80591-5. [DOI] [PubMed] [Google Scholar]
  58. Wahl S. M., Hunt D. A., Wakefield L. M., McCartney-Francis N., Wahl L. M., Roberts A. B., Sporn M. B. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. doi: 10.1073/pnas.84.16.5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Wrann M., Bodmer S., de Martin R., Siepl C., Hofer-Warbinek R., Frei K., Hofer E., Fontana A. T cell suppressor factor from human glioblastoma cells is a 12.5-kd protein closely related to transforming growth factor-beta. EMBO J. 1987 Jun;6(6):1633–1636. doi: 10.1002/j.1460-2075.1987.tb02411.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Yoneda T., Pratt R. M. Mesenchymal cells from the human embryonic palate are highly responsive to epidermal growth factor. Science. 1981 Jul 31;213(4507):563–565. doi: 10.1126/science.7017936. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Cell Biology are provided here courtesy of The Rockefeller University Press

RESOURCES